Poly(ADP-ribose) polymerase family member 14 promotes functional recovery after spinal cord injury through regulating microglia M1/M2 polarization via STAT1/6 pathway
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Published on: January 31, 2018
Ai-Hua Xu1, Yang Yang1, Yang Shao1
1Department of Rehabilitation Medicine, The First Hospital of China Medical University, Shenyang, Liaoning Province, China.
Abstract:
Poly(ADP-ribose)polymerase family member 14 (PARP14), which is an intracellular mono(ADP-ribosyl) transferase, has been reported to promote post-stroke functional recovery, but its role in spinal cord injury (SCI) remains unclear. To investigate this, a T10 spinal cord contusion model was established in C57BL/6 mice, and immediately after the injury PARP14 shRNA-carrying lentivirus was injected 1 mm from the injury site to silence PARP14 expression. We found that PARP14 was up-regulated in the injured spinal cord and that lentivirus-mediated downregulation of PARP14 aggravated functional impairment after injury, accompanied by obvious neuronal apoptosis, severe neuroinflammation, and slight bone loss. Furthermore, PARP14 levels were elevated in microglia after SCI, PARP14 knockdown activated microglia in the spinal cord and promoted a shift from M2-polarized microglia (anti-inflammatory phenotype) to M1-polarized microglia (pro-inflammatory phenotype) that may have been mediated by the signal transducers and activators of transcription (STAT) 1/6 pathway. Next, microglia M1 and M2 polarization were induced in vitro using lipopolysaccharide/interferon-γ and interleukin-4, respectively. The results showed that PARP14 knockdown promoted microglia M1 polarization, accompanied by activation of the STAT1 pathway. In addition, PARP14 overexpression made microglia more prone to M2 polarization and further activated the STAT6 pathway. In conclusion, these findings suggest that PARP14 may improve functional recovery after SCI by regulating the phenotypic transformation of microglia via the STAT1/6 pathway.
Insights
Poly(ADP-ribose)polymerase family member 14 (PARP14) plays a crucial role in spinal cord injury (SCI) recovery. Downregulating PARP14 worsens functional impairment by promoting pro-inflammatory microglia, while its presence aids recovery.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Poly(ADP-ribose)polymerase family member 14 (PARP14) is known to aid functional recovery after stroke.
- The specific role of PARP14 in spinal cord injury (SCI) has not been previously elucidated.
- Understanding PARP14's function in SCI is critical for developing new therapeutic strategies.
Purpose of the Study:
- To investigate the role of PARP14 in the context of spinal cord injury.
- To determine the effect of PARP14 modulation on functional recovery, neuronal apoptosis, neuroinflammation, and microglia polarization after SCI.
- To explore the underlying molecular mechanisms involving the STAT1/6 pathway.
Main Methods:
- Establishment of a T10 spinal cord contusion model in C57BL/6 mice.
- Intra-lesional injection of PARP14 shRNA-carrying lentivirus to silence PARP14 expression.
- In vitro induction of microglia M1 and M2 polarization using specific stimuli.
- Analysis of PARP14 expression, neuronal apoptosis, neuroinflammation, and microglia polarization.
Main Results:
- PARP14 expression was upregulated in the injured spinal cord.
- PARP14 downregulation exacerbated functional deficits, increased neuronal apoptosis, and heightened neuroinflammation.
- PARP14 knockdown promoted M1 microglia polarization (pro-inflammatory) via the STAT1 pathway, whereas PARP14 overexpression favored M2 polarization (anti-inflammatory) through the STAT6 pathway.
Conclusions:
- PARP14 plays a protective role in spinal cord injury.
- PARP14 regulates microglial polarization through the STAT1/6 signaling pathway.
- Targeting PARP14 may represent a promising therapeutic approach for improving functional recovery after SCI.
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